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BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors.

ABSTRACT: Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as epidermal growth factor receptor inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction in cutaneous adverse events with combination therapy is thought to be due to a paradoxical activation of the MAPK pathway by BRAFi in keratinocytes carrying wildtype BRAF. Although treatment options for EGFRi- or MEKi-induced papulopustular eruptions exist, many patients still experience dose reduction, interruption, or discontinuation of EGFRi or MEKi. With the goal of activating MAPK signaling in the skin via BRAFi while minimizing systemic risks, we propose topical BRAFi therapy for the treatment and prevention of papulopustular eruptions due to MAPK pathway inhibitors. If effective, patients will be able to tolerate higher doses of MAPK pathway inhibitors, stay on treatment longer, and achieve better therapeutic outcomes overall.

SUBMITTER: Wang CJ

PROVIDER: S-EPMC7680264 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors.

Wang Catherine J CJ Brownell Isaac I

American journal of clinical dermatology 20201201 6

Inhibitors of the mitogen-activated protein kinase (MAPK) pathway are commonly used in clinical oncology. However, with the exception of BRAF inhibitors (BRAFi), MAPK pathway inhibitors such as epidermal growth factor receptor inhibitors (EGFRi) or MEK inhibitors (MEKi) are associated with dose-limiting papulopustular eruptions. Interestingly, patients treated with a combination of systemic BRAFi and MEKi experience less skin toxicities than patients on monotherapy BRAFi or MEKi. The reduction i ...[more]

PMID: 32720072

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Project description:BackgroundPhosphodiesterase type 4D (PDE4D) breaks down cyclic AMP (cAMP) reducing the signaling of this intracellular second messenger which plays a major role in melanocyte pathophysiology. In advanced melanoma, expression of PDE4D is increased, plays a role in tumor invasion and is negatively associated with survival. In the current work, we investigated the role of PDE4D in the resistance of BRAF-mutated melanoma to mitogen-activated protein kinase (MAPK) pathway-targeted therapy.MethodsEstablished human melanoma cell line sensitive and resistant to BRAF and MEK inhibitors and tumor tissues from melanoma patients were used in this study. Immunoblotting was used to analyze protein expression and quantitative reverse transcription-PCR was used to analyze mRNA expression. DNA methylation analysis was evaluated via bisulfite treatment followed by quantitative PCR. Cell viability was measured by clonogenic assays or spheroid cultures. Cell xenograft experiments in immunodeficient mice were used to validate the results in vivo.ResultsAnalysis of baseline tumors from patients with BRAFV600E-mutated melanoma treated with MAPK inhibitors showed that higher PDE4D expression in situ predicted worse survival in patients. Furthermore, acquired resistance to BRAF and MEK inhibitors was associated with overexpression of PDE4D in situ and ex vivo. The overexpression of the PDE4D5 isoform in melanoma cells resistant to targeted therapies was explained by demethylation or deletion of a CpG island located upstream of the PDE4D5 promoter. We further showed that PDE4D overexpression allowed RAF1 activation, promoting a switch from BRAF to RAF1 isoform in BRAF-mutated melanoma, favoring resistance to BRAF and MEK inhibitors. As a result, pharmacological inhibition of PDE4 activity impeded the proliferation of resistant cells ex vivo and in vivo. The anti-tumorigenic activity of PDE4 inhibitor was achieved via inhibition of the Hippo pathway which plays an important role in resistance to targeted therapies.ConclusionsIn summary, our research showed that PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors and suggests that PDE4 inhibition is a novel therapeutic option for treatment of BRAF-mutated melanoma patients.

Dataset Information

BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors.

Publications

BRAF Inhibitors for the Treatment of Papulopustular Eruptions from MAPK Pathway Inhibitors.

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